Lenalidomide plus rituximab for the initial treatment of frail older patients with DLBCL: the FIL_ReRi phase 2 study

•Rituximab and lenalidomide combination is feasible and has moderate activity in frontline therapy of frail older patients with DLBCL.•The FIL_ReRi trial represents a benchmark for future studies devised for frail patients with DLBCL. [Display omitted] Treatment of diffuse large B-cell lymphoma (DLBCL) in older patients is challenging, especially for those who are not eligible for anthracycline-containing regimens. Fondazione Italiana Linfomi (FIL) started the FIL_ReRi study, a 2-stage single-arm trial to investigate the activity and safety of the chemo-free combination of rituximab and lenalidomide (R2) in ≥70-year-old untreated frail patients with DLBCL. Frailty was prospectively defined using a simplified geriatric assessment tool. Patients were administered a maximum of 6 28-day cycles of 20 mg oral lenalidomide from days 2 to 22 and IV rituximab 375 mg/m2 on day 1, with response assessment after cycles 4 and 6. Patients with partial response or complete response (CR) at cycle 6 were administered lenalidomide 10 mg/d from days 1 to 21 for every 28 cycles for a total of 12 cycles or until progression or unacceptable toxicity. The primary end point was the overall response rate (ORR) after cycle 6; the coprimary end point was the rate of grade 3 or 4 extrahematological toxicity. The ORR was 50.8%, with 27.7% CR. After a median follow-up of 24 months, the median progression-free survival was 14 months, and the 2-year duration of response was 64%. Thirty-four patients experienced extrahematological toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events grade ≥3. The activity of the R2 combination was observed in a significant proportion of subjects, warranting further exploration of a chemo-free approach in frail older patients with DLBCL. This trial was registered at EudraCT as #2015-003371-29 and clinicaltrials.gov as #NCT02955823. Gini et al report on the results of a phase 2 study of rituximab and lenalidomide in 65 frail patients over 70 years of age with diffuse large B-cell lymphoma (DLBCL). Use of this chemotherapy-free combination yielded an overall response rate of 50.8% with 27.7% of patients achieving complete remission. Median progression-free survival was 14 months, and duration of response was 64% at 2 years. Toxicity of grade ≥ 3 occurred in 34 of 65 patients. This chemotherapy-free combination has significant activity and merits further study.